Recurrent Integration of Human Papillomavirus Genomes at Transcriptional Regulatory Hubs
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ABSTRACT:
PROVIDER: PRJNA758985 | ENA |
REPOSITORIES: ENA
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Project description:Oncogenic human papillomavirus (HPV) genomes are often integrated into host chromosomes in HPV-associated cancers. HPV genomes are integrated either as a single copy, or as tandem repeats of viral DNA interspersed with, or without, host DNA. Integration occurs frequently in common fragile sites susceptible to tandem repeat formation, and the flanking or interspersed host DNA often contains transcriptional enhancer elements. When co-amplified with the viral genome, these enhancers can form super-enhancer-like elements that drive high viral oncogene expression. Here, we compiled highly curated datasets of HPV integration sites in cervical (CESC) and head and neck squamous cell carcinoma (HNSCC) cancers and assessed the number of breakpoints, viral transcriptional activity, and host genome copy number at each insertion site. Tumors frequently contained multiple distinct HPV integration sites, but often only one “driver” site that expressed viral RNA. Since common fragile sites and active enhancer elements are cell-type specific, we mapped these regions in cervical cell lines using FANCD2 and Brd4/H3K27ac ChIP-seq, respectively. Large enhancer clusters, or super-enhancers, were also defined using the Brd4/H3K27ac ChIP-seq dataset. HPV integration breakpoints were enriched at both FANCD2-associated fragile sites, and enhancer-rich regions, and frequently showed adjacent focal DNA amplification in CESC samples. We identified recurrent integration “hotspots” that were enriched for super-enhancers, some of which function as regulatory hubs for cell-identity genes. We propose that during persistent infection, extrachromosomal HPV minichromosomes associate with these transcriptional epicenters, and accidental integration could promote viral oncogene expression and carcinogenesis.
2021-09-01 | GSE183048 | GEO
Project description:Oncogenic human papillomavirus (HPV) genomes are often integrated into host chromosomes in HPV-associated cancers. HPV genomes are integrated either as a single copy or as tandem repeats of viral DNA interspersed with, or without, host DNA. Integration occurs frequently in common fragile sites susceptible to tandem repeat formation and the flanking or interspersed host DNA often contains transcriptional enhancer elements. When co-amplified with the viral genome, these enhancers can form super-enhancer-like elements that drive high viral oncogene expression. Here we compiled highly curated datasets of HPV integration sites in cervical (CESC) and head and neck squamous cell carcinoma (HNSCC) cancers, and assessed the number of breakpoints, viral transcriptional activity, and host genome copy number at each insertion site. Tumors frequently contained multiple distinct HPV integration sites but often only one "driver" site that expressed viral RNA. As common fragile sites and active enhancer elements are cell-type-specific, we mapped these regions in cervical cell lines using FANCD2 and Brd4/H3K27ac ChIP-seq, respectively. Large enhancer clusters, or super-enhancers, were also defined using the Brd4/H3K27ac ChIP-seq dataset. HPV integration breakpoints were enriched at both FANCD2-associated fragile sites and enhancer-rich regions, and frequently showed adjacent focal DNA amplification in CESC samples. We identified recurrent integration "hotspots" that were enriched for super-enhancers, some of which function as regulatory hubs for cell-identity genes. We propose that during persistent infection, extrachromosomal HPV minichromosomes associate with these transcriptional epicenters and accidental integration could promote viral oncogene expression and carcinogenesis.
| S-EPMC8632991 | biostudies-literature
Project description:Integration of human papillomavirus (HPV) DNA into the host genome is a critical aetiological event in the progression from normal cervix to intraepithelial neoplasm, and finally to invasive cervical cancer. In this study, we want to know how HPV DNA physical status relates to treatment outcome for cervical carcinomas.
2013-07-28 | GSE49288 | GEO
Project description:Integration of human papillomavirus (HPV) DNA into the host genome is a critical aetiological event in the progression from normal cervix to intraepithelial neoplasm, and finally to invasive cervical cancer. In this study, we want to know how HPV DNA physical status relates to treatment outcome for cervical carcinomas. Cervical cancer samples were compared with normal sample. And also, we divided 39 cervical cancer patients into four groups according to HPV DNA physical status and investigated differentially expressed gene profiles in these groups using Agilent two-color experiment.
2013-07-28 | E-GEOD-49288 | biostudies-arrayexpress
Project description:We report that the integration of the human papillomavirus into the host genome increases chromatin accessibility, transcription, and CTCF binding within 100 kbp of the integration site which promotes oncogenesis in some patients.
2020-02-14 | GSE143026 | GEO
Project description:Human papillomavirus (HPV) infection drives the development of some head and neck cancer squamous cell carcinomas (HNSC). Although these tumors are sensitive to treatment, ~10% of patients fail therapy. However, the mechanisms that underlie treatment failure remain unclear. Here, we assessed the transcriptional profiles of 10 paired primary and subsequent recurrent HPV-related oropharyngeal squamous cell carcinomas (OPSCCs) using an exome-capture hybrid RNA sequencing assay. Principal componenent analysis using the expression data from the top 500 most variable genes revealed that 29.3% of the variance was aassociated with tumor status (i.e., primary vs recurrent tumor). Four of the primary/recurrent tumor pairs demonstrated greater clustering based on the patient of origin rather than the tumor status (primary vs recurrent). Additionally, two of the recurrences were distant, two were local, and the remaining six were regional. The recurrent tumors did not cluster necessairly based on site of recurrence. Unsupervised heirarchical clustering of the top 500 most variable genes revealed a correlation between recurrent tumors and metabolic gene expression while the primary tumors demonstrated increased expression in several immunologic related genes, mitogenic signaling, and epigenetic signaling genes. Using the PANTHER GO-Slim biological process pathway analysis, we identified enrichment of processes involved in biosynthesis, metabolism including oxidative phosphorylation, and Wnt signaling. Using gene set enrichment analysis, we observed enrichment in oxidative phosphorylation, fatty acid metabolism, and glutathione metabolism as well as MYC, P53-dependent DNA damage repair, and NRF2 pathway gene expression among the recurrent HPV-associated OPSCCs.
2021-02-02 | GSE165883 | GEO
Project description:Characterisation and diversity of complete human papillomavirus genomes in cervical swabs using next-generation sequencing
| PRJEB39467 | ENA